Article
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
Affiliations
Organisations
- (1) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- (2) QIMR Berghofer Medical Research Institute, grid.1049.c
- (3) Cyprus Institute of Neurology and Genetics, grid.417705.0
- (4) University of Cambridge, grid.5335.0
- (5) Vanderbilt University, grid.152326.1
- (6) Harvard University, grid.38142.3c
- (7) Brigham and Women's Hospital, grid.62560.37
- (8) Dana-Farber Cancer Institute, grid.65499.37
- (9) Mount Sinai Hospital, grid.416166.2
- (10) University of Toronto, grid.17063.33
- (11) University of California, Irvine, grid.266093.8
- (12) German Cancer Research Center, grid.7497.d
- (13) Queen's University, grid.410356.5
- (14) University of Wisconsin–Milwaukee, grid.267468.9
- (15) Fred Hutchinson Cancer Research Center, grid.270240.3
- (16) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- (17) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
- (18) Spanish National Cancer Research Centre, grid.7719.8
- (19) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
- (20) Hannover Medical School, grid.10423.34
- (21) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (22) Örebro University, grid.15895.30
- (23) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
- (24) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (25) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (26) University of Copenhagen, grid.5254.6, KU
- (27) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
- (28) University of Tübingen, grid.10392.39
- (29) National Cancer Institute, grid.48336.3a
- (30) Lund University, grid.4514.4
- (31) Heidelberg University, grid.7700.0
- (32) Hospital Clínico San Carlos, grid.411068.a
- (33) American Cancer Society, grid.422418.9
- (34) Oncology and Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
- (35) University Cancer Center Hamburg, grid.412315.0
- (36) University of Florida, grid.15276.37
- (37) University of Sydney, grid.1013.3
- (38) Erasmus University Medical Center, grid.5645.2
- (39) Antoni van Leeuwenhoek Hospital, grid.430814.a
- (40) Mayo Clinic, grid.66875.3a
- (41) Cancer Center of Lyon, grid.462282.8
- (42) Imperial College London, grid.7445.2
- (43) University of Sheffield, grid.11835.3e
- (44) Karolinska Institute, grid.4714.6
- (45) Temple University Health System, grid.412530.1
- (46) Leiden University Medical Center, grid.10419.3d
- (47) Johns Hopkins University, grid.21107.35
- (48) London School of Hygiene & Tropical Medicine, grid.8991.9
- (49) McGill University Health Centre, grid.63984.30
- (50) University of Westminster, grid.12896.34
- (51) University of Southampton, grid.5491.9
- (52) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- (53) Leipzig University, grid.9647.c
- (54) University of California, Los Angeles, grid.19006.3e
- (55) University of Edinburgh, grid.4305.2
- (56) University Medical Center Hamburg-Eppendorf, grid.13648.38
- (57) Institute of Cancer Research, grid.18886.3f
- (58) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- (59) Curtin University, grid.1032.0
- (60) Complejo Hospitalario Universitario de Santiago, grid.411048.8
- (61) University of California, San Diego, grid.266100.3
- (62) Cancer Council Victoria, grid.3263.4
- (63) University of Melbourne, grid.1008.9
- (64) McGill University, grid.14709.3b
- (65) University of Utah, grid.223827.e
- (66) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
- (67) University Hospital Cologne, grid.411097.a
- (68) University of Cologne, grid.6190.e
- (69) University of Southern California, grid.42505.36
- (70) Stockholm South General Hospital, grid.416648.9
- (71) Frederick National Laboratory for Cancer Research, grid.418021.e
- (72) University of Oxford, grid.4991.5
- (73) Pomeranian Medical University, grid.107950.a
- (74) University Hospital Ulm, grid.410712.1
- (75) Cancer Prevention Institute of California, grid.280669.3
- (76) Stanford University, grid.168010.e
- (77) National University of Ireland, Galway, grid.6142.1
- (78) Bashkir State University, grid.77269.3d
- (79) Kuopio University Hospital, grid.410705.7
- (80) University of Eastern Finland, grid.9668.1
- (81) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
- (82) Oslo University Hospital, grid.55325.34
- (83) University of Oslo, grid.5510.1
- (84) Flanders Institute for Biotechnology, grid.11486.3a
- (85) KU Leuven, grid.5596.f
- (86) University of Hawaii at Manoa, grid.410445.0
- (87) Genome Institute of Singapore, grid.418377.e
- (88) University of Washington, grid.34477.33
- (89) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
- (90) German Breast group, grid.434440.3
- (91) Macedonian Academy of Sciences and Arts, grid.419383.4
- (92) Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- (93) University Hospital of Heraklion, grid.412481.a
- (94) VU University Medical Center, grid.16872.3a
- (95) Technical University of Munich, grid.6936.a
- (96) University College London, grid.83440.3b
- (97) University Health Network, grid.231844.8
- (98) City Of Hope National Medical Center, grid.410425.6
- (99) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- (100) Universitair Ziekenhuis Leuven, grid.410569.f
- (101) Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL, USA
- (102) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
- (103) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
- (104) University of Oulu, grid.10858.34
- (105) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
- (106) Carmel Medical Center, grid.413469.d
- (107) Hospital Universitario Puerta de Hierro Majadahonda, grid.73221.35
- (108) Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
- (109) King's College London, grid.13097.3c
- (110) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
- (111) John Hunter Hospital, grid.414724.0
- (112) University of Newcastle Australia, grid.266842.c
- (113) BC Cancer Agency, grid.248762.d
- (114) University of British Columbia, grid.17091.3e
- (115) Royal Women's Hospital, grid.416259.d
- (116) University of Western Australia, grid.1012.2
- (117) Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
- (118) Columbia University, grid.21729.3f
- (119) McGill University and Génome Québec Innovation Centre, grid.411640.6
- (120) Pontificia Universidad Javeriana, grid.41312.35
- (121) Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany
- (122) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
- (123) University of California, San Francisco, grid.266102.1
Description
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
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